Our initial focus was on MCD, a syndrome in which infected B cells are in the lytic phase of the viral replication cycle. Infected cells express several KSHV structural glycoproteins at the surface, including gH/gL, gB, and K8.1A. Though a relatively rare disease, MCD incidence continues to rise despite antiretroviral therapy and the associated improvements in immune function. MCD if a life-threatening disease (median life expectancy <3 years after diagnosis), and no standards for clinical management have been developed. Hence immunotoxins to selectively kill infected B cells may prove beneficial. We initially reported the design and characterization of an immunotoxin, YC15-PE38, that potently killed a gH transfectant cell line and strongly inhibited infectious virus production from Vero-219 cells harboring an episomal infectious KSHV genome with EGFP and RFP that serve as reporters for latent and lytic infection, respectively. We subsequently produced another immunotoxin, 2014-PE38, against the KSHV 8.1A glycoprotein, which is expressed earlier than gH as cells enter the lytic phase of replication. This immunotoxin potently inhibited infectious virus production from Vero-219 by selectively killing the virus-producing cells, and synergistically complemented the activity of ganciclovir. Oddly, neither YC15-PE38 or 2014-PE38 were active against several chronically infected human PEL cell lines tested, based on both direct cell killing assays and measurements of effects on virus release. Whether this represents an unusual feature of PEL-derived cells, or is characteristic of all KSHV-infected B cell types, remains an important unanswered question.